The World Health Organization (WHO) estimates that 35 million people worldwide are living with HIV infections. Improved therapeutic control of viral replication has significantly increased the number of individuals living with chronic HIV infection An unintended consequence of shifting HIV from a more acute to chronic infection is the emergence of a number of co-morbidities that complicate clinical management of HIV-positive individuals. Lipid metabolic dysfunction (e.g., hyperlipidemia and lipodystrophy) in HIV-positive individuals appears to be driven by both HIV and anti-retroviral therapies (HAART)). Perhaps not surprisingly, coronary artery disease and atherosclerosis have become a major comorbidity for those individuals being treated for HIV with HAART. The molecular mechanisms underlying the crosstalk between HIV infection, dyslipidemia and chronic inflammation remain poorly understood. The Sterol Regulatory Element Binding Proteins (SREBPs) are key transcriptional regulators of cellular and whole body lipid homeostasis through their ability to transactivate 40+ genes involved in lipid biosynthesis, lipoprotein import, intracellular lipid transport and storage Genetic disruption of SREBPs results in severe perturbations in cellular lipid homeostasis and inflammation. Studies indicate that HIV infections upregulate the SREBP pathway, presumably to support the lipid biosynthetic requirements of viral replication. Conversely, type I IFN signaling downregulates SREBP activity in immune cells, presumably to control viral replication, suggest an important role for SREBP transcriptional axis in HIV immunity. Consistent with this, we find that genetic perturbations in the ability of a cell to activate SREBPs render macrophages resistant to HIV infection. The experiments proposed in this R21 application are designed to extend on these intriguing preliminary observations and define the molecular mechanisms by which the SREBP transcriptional program influences active HIV infection. Additionally, we will determine if reprogramming cellular lipid metabolism through the SREBP axis could serve as novel approach for re-activation of latent infection. The results of these studies could provide important mechanistic insights into the relationship between HIV driven metabolic programming and could point to potential therapeutic opportunities to both attenuate HIV infection, and correct lipid dysfunction.